Doxorubicin（DOX）是一种用于治疗多种癌症的有效化疗药物。但是，心脏毒性副作用限制了其在临床上的应用，其中铁死亡在DOX诱导的心脏毒性中起着至关重要的病理机制。 Na + / K + ATP酶（NKA）活性的降低与DIC进展密切相关。然而，NKA功能异常是否涉及DOX诱导的心脏毒性和铁死亡仍然不清楚。在这里，我们旨在揭示DOX诱导的铁死亡中NKA功能不良的细胞和分子机制，并将NKA作为DIC的潜在治疗靶点进行研究。 NKAα1半合子小鼠中NKA的降低活性进一步加剧了DOX触发的心脏功能障碍和铁死亡。相反，针对NKAα亚单位（DR-Ab）的抗体减轻了DOX引起的心脏功能障碍和铁死亡。从机制上讲，NKAα1与SLC7A11相互作用形成了一种新的蛋白质复合物，直接涉及DIC的疾病进展。此外，DR-Ab对DIC的治疗作用是通过促进NKAα1 / SLC7A11复合物的结合并维持SLC7A11在细胞表面的稳定性来减少铁死亡来介导的。这些结果表明，针对NKA的DR区域的抗体可能作为减轻DOX诱导的心脏毒性的一种新的治疗策略。版权所有©2023，由Elsevier Inc.发表。

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.Copyright © 2023. Published by Elsevier Inc.